Abstract

The giant cell tumor of bone (GCT) is a benign bone-destructive neoplasm, with uncertain biological behavior, with features such as a large number of multinucleated giant cells and aggressive behavior. The local recurrence of GCT is often observed, especially in the first three years after treatment, giving a rate of recurrence ranging from 20% to 50% of cases. Further aggravating the recurrence, is the fact that after a relapse, patients often also presents metastasis in other organs, mainly in the lungs. In this study we investigate the expressions of epithelial and mesenchymal (EMT) markers (ADAM23, CDH1, CDH3, MMP14, p16, TIMP2 and VIM) in GCTs by quantitative qPCR. The expression of the MMP14, TIMP2 and VIM genes increased in more than 96% samples and ADAM23, CDH1, CDH3 and p16 genes had expression reduced in more than 91% of GCTs samples. Since ADAM23, CDH1, CDH3 and p16 have CpG islands in their promoter regions and low expression in tumor tissue, their methylation patterns were analyzed by MSP-PCR. For ADAM23 and p16 genes were detected a high frequency of hypermethylation. The lower expression of ADAM23 and p16 are directly related to the recurrence and metastasis in GCTs. The genes MMP14, TIMP2 and VIM are related to angiogenesis, degradation of extracellular matrix and cell migration and presented with increased expression in GCT, also confirmed by immunohistochemistry. These observations suggest that dysregulation of these genes may be a key factor responsible for the initiation and perpetuation of EMT in GCT, leading to cellular migration and malignant transformation, contributing to development of metastases and tumor progression.